1. Field of the Invention
The present invention relates to improved drug delivery apparatus, and to the use of improved drug formulations for delivery by the apparatus.
2. Description of the Related Art
A number of drugs have been used for the treatment of patients with respiratory disorders. Antiproteinase inhibitors, such as Prolastin®, are being studied and used in the treatment of inflammatory lung disease and approved for use in congenital emphysema. Prostacylins/prostacylin analogs, such as Iloprost, are used in the treatment of pulmonary hypertension. Mucoactive drugs, such as Pulmozyme® (recombinant, human DNase) and SuperVent®™ are used and studied in the treatment of patients with cystic fibrosis lung disease. Gamma interferon is being studied for use in the treatment of pulmonary fibrosis and tuberculosis. Immunosuppressants, such as cylosporine, are being studied for the prevention of lung organ rejection. The Interferons, specific monoclonal antibodies, directed against tumor-associated antigens, receptors or oncogene proteins, and adenovirus-directed gene therapeutics, are used and studied as a treatment for various lung cancers.
Beta2 adrenergic bronchodilators, such as Ventolin®, Albuterol® and Salbutamol®, are indicated for the prevention and relief of bronchospasm. Corticosteroids, such as Budesonide®, are used in the treatment of inflammatory lung and reactive airways disease such as asthma. Surfactants, such as Exosurf®, Survanta® and Surfaxin™, are used to treat infant respiratory distress syndrome and are being studied as therapies in certain lung inflammatory diseases, such as chronic bronchitis and cystic fibrosis. Anti-infective agents [e.g., antibacterial (e.g., tobramycin); antifungal (e.g., AmBiosome®); and antiviral (e.g., Synagis™, Virazole®, the Interferons and vaccines)] are used to control pulmonary infections, particularly in subjects who are at risk, such as children, the elderly and the immunocompromised and in patients suffering for example with cystic fibrosis lung disease. These latter patients are prone to acute and chronic endobronchial infections, typically caused by the gram-negative bacterium, Pseudomonas aeruginosa. Pseudomonas infections are treated with the antimicrobial polypeptide, Colistin and the aminoglycoside antibiotic, Tobramycin.
WO 96/12471 discloses the use of an aminoglycoside formulation (Tobramycin) for aerosolisation. The formulation comprises from about 200 mg to about 400 of aminoglycoside dissolved in about 5 ml of solution containing about 0.225% of sodium chloride. The formulation has a pH of between about 5.5 to 6.5 and is administered by aerosolisation. This formulation suppresses and inhibits at least 95% of susceptible bacteria in the endobronchial space of a patient suffering from the endobronchial infection.
Various drug delivery apparatus are suitable for delivering such drugs in atomised form. For example, a jet-type nebuliser is disclosed in WO 96/12471 as being suitable for aerosolisation of the aminoglycoside solution. This nebulises the formulation into an aerosol having a particle size predominantly in the range of 1 to 5 μm. A limited number of nebulisers are suitable for nebulising this formulation. Also, formulations of this kind have quite a large volume, and must be delivered over more than one breath.
The suitable jet-type nebuliser is shown in FIG. 3 of WO 96/12471, and consists of a case, a mouthpiece, a nebuliser cup covered with a cap, a venturi chamber, an air supply tube and a baffle. The liquid formulation is placed in the nebuliser cup, and an air supply tube is connected to it. The pressurised air passes from the cup into a jet nebuliser orifice where an aerosol is created by shearing the liquid solution into small threads of liquid that shatter into small particles when they hit the baffle. As a patient inhales through the mouthpiece, air is drawn in through air intake holes in the cap into the venturi chamber where it mixes with the aerosol and is carried to the patient.
All of the nebulisers disclosed are continuously operating nebulisers which generate an aerosol continuously.
In addition, WO 96/12471 mentions a study of the use of nebulisers to determine the pharmacodynamics of aminoglycoside in the sputum of patients which is a measure of the efficacy of the aerosol delivery. Such jet nebulisers were found to be about 10% efficient under clinical conditions, although the amount deposited and absorbed in the lungs is only a fraction of that 10%. Thus, large quantities of the drug must be used if the required dosage of the formulation is to reach the patient. For this reason, the prior art document is directed to a formulation comprising from about 200 mg to about 400 mg of aminoglycoside dissolved in about 5 mls of solution. This is a large mass of drug to be delivered to a patient, and it means that the treatment must be delivered over a number of inhalations lasting maybe several minutes. An example of ten to thirteen minutes to deliver 300 mgs is given. Single inhalation atomisers, as disclosed in WO 96/09085 and WO 96/13292, are limited to a maximum drug mass per inhalation of less than 10 mgs. Such atomisers are, therefore, not suitable for delivering antibiotics.
Other suitable nebulisers are mesh type nebulisers.
Some drugs, including antibiotics, give no direct feedback to the patient on their effectiveness at the time of inhalation, unlike a bronchodilator for asthmatics which has an immediate effect in easing the patient's symptoms. Further, the inhalation of aerosols, even when appropriately formulated for pH and tonicity may still cause bronchial constriction and coughing in patients. As a result, the patient has no real idea of how much of the drug has been delivered. He or she merely continues to inhale the atomised substance until there is none left.
In a recent study, the connection between the duty cycle in vitro and the inhaled dose during domiciliary nebuliser use has been investigated. The effectiveness of domiciliary nebuliser therapy is determined by the adherence to a prescribed regimen, the deposition of the drug in the appropriate area of the lungs, and the breathing pattern during nebulisation. The breathing pattern of patients was measured in the laboratory, and from those measurements the patient's duty cycle was calculated. The duty cycle is the proportion of the time the patient spends in inspiration and this normally falls in the range of 0.3 to 0.5. If the patient is inhaling aerosol from a nebuliser, then the amount of aerosol that he or she inhales is directly proportional to his duty cycle. This has been confirmed by measurement of the inhaled dose on a filter during testing, and also using lung scintigraphy.
When similar measurements are made during domiciliary nebuliser use, the duty cycle recorded is significantly less than that recorded in the laboratory. This is because the nebuliser output is continuous and patients interrupt their treatment to rest, talk, drink or as a result of disease related symptoms such as coughing. This reduces the amount of drug inspired by the patient. In addition, using the duty cycle to measure dosage does not take account of whether or not the patient has a good inhalation method, nor whether the patient is adherent to that treatment regimen, for example taking the number of treatments prescribed by their doctor. This makes it particularly difficult to assess why a patient does not respond to the treatment, because the doctor does not know whether it is because the patient is not complying with the regimen prescribed, because the patient is not inhaling properly from the delivery system, or because the drug is ineffective. It is quite clear from various studies that a very high proportion of patients are not adherent to their treatment regimen.
Clearly, if the domiciliary duty cycle is much less than the duty cycle measured in a laboratory, the patient is receiving significantly less of the prescribed drug. In addition, a poor inhalation method by the patient and failure to comply with the regimen farther reduce the amount of drug received in the lungs of the patient. The percentage of the predicted dose actually received by the lungs of the patient varies enormously. Typically, less than 10% of the initial volume of drug placed in a nebuliser reaches a patient's lungs in domiciliary use. Thus, it is clear that something of the order of ten times as much of the drug is required to be atomised as actually reaches the patient's lungs.
A number of different types of apparatus for delivering a drug into the lungs of a patient are known. The pneumatic or jet-type nebuliser is particularly effective in supplying an aerosolised drug for inhalation, but other types of nebulisers are available, such as the ultrasonic-type nebuliser in which the drug to be atomised is forced through a mesh by a vibrating piezo-electric crystal whereupon the droplets passing through the mesh are entrained in the air being inhaled by the patient. The mesh gauge determines the size of the droplets which enter the air stream. Alternatively, a dosimetric spacer can be used. When using a spacer, the drug is introduced into the holding chamber of the spacer either in aerosolised form, or by loading the air within the holding chamber with the drug in powdered form. The patient then breathes from the holding chamber, thereby inhaling the drug-laden air. Such spacers are particularly effective when treating children or elderly patients, and for use with certain drugs. The drug is normally delivered over a number of breaths. Of course, the concentration of the drug in each breath decreases over time as a result of dilution caused by ambient air entering the holding chamber to replace air being inhaled by the patient, and as a result of the deposition of the drug within the chamber.